PegIFN + RBV

Report
Direct Acting Antivirals
for Chronic Hepatitis C
Sheng-Shun Yang, M.D., Ph.D.
Division of Gastroenterology & Hepatology,
Department of Internal Medicine,
Taichung Veterans General Hospital, Taichung, Taiwan
2013-11-28
1
C型肝炎病毒感染之併發症

慢性C型肝炎是導致肝病重要的原因[1]
– 1/4 of the ~500,000 new HCC cases identified globally each
year are attributable to HCV[2]

預估未來幾年,C型肝炎相關的併發症增加兩倍[3]

C型肝炎感染經常合併許多肝外疾病或症候[4]
– Mixed cryoglobulinemia vasculitis, lymphoproliferative
disorders, diabetes (2-3 ↑ odds), renal disease, rheumatoid
arthritis–like polyarthritis, sicca syndrome, depression,
neurocognitive impairment
1. Lavanchy D. Clin Microbiol Infect 2011;17:107-115.
2. Montalto G, et al. Ann NY Acad Sci 2002;963: 13-20.
3. Milliman, Inc. Consequences of HCV: costs of a baby boomer epidemic, 2009.
4. Jacobson IM, et al. Clin Gastroenterol Hepatol 2010;8:1017-1029.
治療C型肝炎的目標

首要目標乃是根除此病毒

次要目標
•
•
•
•
•
•
Slow disease progression
Minimize risk of liver cancer
Improve liver damage
Enhance quality of life
Prevent transmission of virus
Reduce extra-hepatic manifestations
Outline

國內當前標準療法 (standard of care)

DAAs 新藥介紹
- 已上市 (Boceprevir & Telaprevir)
- 即將上市 (Sofosbuvir & Simeprevir)
- 研發中藥物
慢性C型肝炎治療里程碑
Sustained Virologic Response (%)
100
SVR rates remain suboptimal in HCV genotype 1
Direct acting
antivirals (DAAs):
~2011
IL28B genotypes:
~2009
80
Response-guided therapy (RGT):
~2004
60
45-47%
40
68-75%
54-63%
38-43%
31-35%
13-19%
20
6%
0
IFN 6m
1992
IFN 12m
IFN / RBV 6 m
IFN / RBV 12m
2001-2010
PEG-IFN 12m
PEG-IFN / RBV
12m
PEG-IFN / RBV /
DAA 12m
2011
治療C型肝炎之病毒動力學
SVR Is Durable & Beneficial
“These patients should be considered as cured”
• 99.1% HCV RNA undetectable independent of population
- Elevated ALT, persistently normal ALT, immunocompromised
• Independent of treatment by
- IFN monotherapy, IFN/RBV, IFN/RBV/DAAs
• 34-61% reverse cirrhosis
• ~90% improve fibrosis
• Improved neurocognitive function, fatigue; reduces insulin
resistance
• Reduces risk of HCC and improves liver & all-cause mortality
Camma et al. Hepatology 2004;39(2):333-42; D’ Ambrosio et al. Hepatology 2012;56:532-43
Kraus MR, et al. Hepatology 2013;58:497-504; Brandman et al. Diabetes Care 2012;35(5):1090-4
Van der Maar, et al. JAMA 2012;308:2584-93.
• ISDR in NS5A
• IL28B SNPs
宿主IL28B基因多型性

Genetic polymorphism near IL28B, which encodes for IFN lambda-3
– CC genotype 對當前標準療法有較佳的治療反應 (基因第一型病毒)
Ge D, et al. Nature. 2009;461:399-401.
當前C型肝炎標準療法及療效
IFN Monotherapy
SVR, %
PegIFN
PegIFN + RBV
(Taiwan)
PegIFN
+ RBV
(West)
24 wks
48 wks
78 wks
All genotypes
6-19
11-19
10-22
18-39
--
--
GT1 (48 wks)
--
--
--
--
75-80
42-46
GT2/3 (24 wks)
--
--
--
--
85-90
76-82
Modified from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
目前治療成效不錯
我們還需要 DAAs嗎?
Multiple AEs from SOC
Null/partial responders, relapsers
Unwilling, intolerant, ineligible
‘Difficulty-to-treat’ (cirrhotics, HIV coinfected, post LT
recurrent, renal transplant candidates & HCV infected post
kidney transplantation)
部分地區或國家上市DAAs
Boceprevir (BOC)
Telaprevir (TVR)
限定基因第一型:
標準療法 (P/R) + C肝病毒蛋白酶抑制劑 (PI)
使用於過去未曾治療過 (naïve) 的病患
Telaprevir + pegIFN/RBV
用於基因第一型未曾治療過的病患
Dosage and Administration

750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (not low fat; standard fat meal is 21 g, eg,
1/2 cup nuts or 2 oz cheddar cheese)

Must be administered with both pegIFN and RBV; telaprevir dose must not be reduced or interrupted
TVR + PegIFN + RBV
0
4
PegIFN + RBV
12
Wks
eRVR; stop at Wk 24, f/u 24 wks
No eRVR; PegIFN + RBV F/u
24 wks
24
48
Response-Guided Therapy
HCV RNA
TVR + PegIFN/RBV
PegIFN/RBV
Total
Duration
Undetectable* at wks 4 and 12
First 12 wks
Additional 12 wks
24 wks
Detectable (but ≤ 1000 IU/mL) at wks 4 and/or 12
First 12 wks
Additional 36 wks
48 wks

Treatment-naïve patients with compensated cirrhosis and eRVR may benefit from additional 36 wks
of pegIFN + RBV (ie, to wk 48)
*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
Telaprevir [package insert]. May 2011. Vertex/Johnson & Johnson's Incivo.
Telaprevir + PR:
基因第一型未曾治療過的病患之持續病毒反應率
ADVANCE: TVR + PegIFN/RBV in Treatment-Naïve Genotype 1
100
P < .001
SVR (%)
80
T12PR
PR
75
60
44
40
20
0
n/N =
271/363
Jacobson IM, et al. NEJM 2011;364:2405-2416.
158/361
SVR
Telaprevir + PR: 副作用
 Higher rates of rash, anemia, and anorectal signs/symptoms in TVR
arms vs control
Adverse Event, %
TVR + PR RGT/48*
(n = 1797)
PR48
(n = 493)
Rash
56
34
Anemia†
36
17
Anorectal events
29
7
*Results from patients with 8 wks and 12 wks of TVR exposure pooled. Anemia rates from
T12 groups estimated to be ~ 40%.
†Anemia was managed with RBV dose modification; epoetin alfa was not permitted in
clinical trials.
 Anorectal symptom management
– Fiber, loperamide, hydrocortisone, and pramoxine topical cream
Telaprevir package insert. May 2011.
Boceprevir + PR
使用於基因第一型未曾治療過者
Dosage and Administration



800 mg (four 200-mg capsules) TID (every 7-9 hrs) with food (meal or light snack)
Must be administered with both pegIFN and RBV
Boceprevir dose must not be reduced or interrupted
F/u
Boceprevir + PegIFN + RBV
24 wks
PegIFN
+ RBV
PegIFN + RBV
Boceprevir + PegIFN + RBV
0
4
8
Response-Guided Therapy*





12
24
Wks
28
36
F/u
24 wks
48
If undetectable at wks 8 and 24, continue 3-drug regimen to wk 28
If detectable at wk 8, but undetectable at wk 24, continue 3-drug regimen to wk 36, then administer
pegIFN/RBV to wk 48
All cirrhotic patients should receive lead-in followed by pegIFN/RBV + boceprevir for 44 wks
Futility: stop all 3 drugs if wk 12 HCV RNA ≥ 100 IU/mL or wk 24 HCV RNA detectable
Wk 4 < 1 log HCV RNA reduction associated with greater risk of developing resistance and lower
SVR rates: consider pegIFN/RBV + boceprevir for 44 wks after lead-in, no RGT
*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
Boceprevir [package insert]. May 2011. Merck & Co’s Victrelis.
Boceprevir + PR:
持續病毒反應率
SPRINT-2: BOC + PegIFN/RBV in Genotype 1 Treatment-Naïve Patients
P < .001
P < .001
100
60
40
40
20
n/N =
0
80
68
67
SVR (%)
SVR (%)
80
P = .004
100
125/
311
211/
316
213/
311
PR48
BOC RGT
BOC/PR48
Nonblack Patients
Poordad F, et al. NEJM 2011;364:1195-1206.
P = .04
53
60
42
40
23
20
n/N =
0
12/
52
22/
52
29/
55
PR48
BOC RGT
BOC/PR48
Black Patients
Boceprevir + PR: 副作用
 Significantly higher rates of anemia, neutropenia, and
dysgeusia in boceprevir arms vs control
Adverse Event, %
Boceprevir + PR RGT/48
(n = 1225)
PR48
(n = 467)
Anemia*
50
30
Neutropenia
25
19
Dysgeusia
35
16
*Anemia was managed with RBV reduction and/or epoetin alfa (43% of boceprevir + PR and
24% PR).
Boceprevir [package insert]. May 2011.
Triple Therapy
使用於基因第一型過去治療失敗者
Telaprevir + PR:基因第一型過去治療失敗者
Dosage and Administration

750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (not low fat;
standard fat meal is 21 g, eg, 1/2 cup nuts or 2 oz cheddar cheese)

Must be administered with both pegIFN and RBV

Telaprevir dose must not be reduced or interrupted
TVR + PegIFN + RBV
0
4
Treatment duration
F/u
24
wks
PegIFN + RBV
12
Wks
24
48

All previous partial responders or null responders receive 12 wks of triple
therapy followed by 36 wks of pegIFN/RBV

Previous relapsers follow the same response-guided approach as
treatment-naive patients
Telaprevir [package insert]. May 2011.
Telaprevir使用於過去治療失敗者的療效
REALIZE: TVR + PegIFN/RBV in Genotype 1 Previous Relapsers and Nonresponders
 Lead-in examined, but found to have no impact on response and not used in TVR label
T12/PR48
100
Previous Relapsers
83*
88*
LI T12/PR48
Pbo/PR48
Previous Partial
Responders
Previous Null
Responders
SVR (%)
80
59*
60
54*
40
29*
24
15
20
n/N =
33*
121/145
124/141
16/68
0
*P < .001 vs placebo/PR48.
Zeuzem S, et al. NEJM 2011;364:2417-2428.
29/49
26/48
4/27
5
21/72
25/75
2/37
Boceprevir + PR用於基因第一型過去治療失敗之
無肝硬化患者
Dosage and Administration
 800 mg (four 200-mg capsules) TID (every 7-9 hrs) with food (meal or light snack)
 Must be administered with both pegIFN and RBV
 Boceprevir dose must not be
reduced or
interrupted
Boceprevir
+ PegIFN
+ RBV
PegIFN
+ RBV
Boceprevir + PegIFN + RBV
PegIFN + RBV
0
4
8
12
24
Wks
28
36
F/u
24
wks
48
Partial Responders, Relapsers: Duration Based on Wks 8 and 24 HCV RNA*
 If undetectable at both time points, continue 3-drug regimen to Wk 36
 If detectable at Wk 8 but undetectable at Wk 24, continue 3-drug regimen to Wk 36, then administer
pegIFN/RBV to Wk 48
 All cirrhotic patients should receive lead-in then boceprevir + PR for 44 wks
 Futility: stop all 3 drugs if Wk 12 HCV RNA ≥ 100 IU/mL or Wk 24 HCV RNA detectable
 Wk 4 < 1 log HCV RNA reduction associated with greater risk of developing resistance associated
variants and lower SVR rates: consider boceprevir + PR for 44 wks after lead-in, no RGT
 If considered for treatment, previous null responders should receive lead-in then boceprevir + PR for
44 wks
*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
Boceprevir [package insert]. May 2011.
BOC + PR: SVR by Historical Response
(Partial Responders and Relapsers*)
RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients
100
SVR (%)
80
69
60
52
40
40
20
n/N =
0
75
PR48 (n = 80)
BOC RGT (n = 162)
BOC/PR48 (n = 161)
29
7
2/29 23/57 30/58
2/29 23/57 30/58
Partial Responder
Relapser
*Partial responders had a decrease in plasma HCV RNA of at least 2 log10 by Wk 12 of previous therapy
but with detectable HCV RNA throughout the course of therapy. Relapsers had undetectable HCV RNA at
end of previous therapy without subsequent attainment of SVR.
Bacon BR, et al. NEJM 2011;364:1207-1217.
CUPIC: Telaprevir or Boceprevir + P/R
in GT 1 Treatment-Experienced Cirrhotics

French compassionate use program for early access to TVR and BOC
before approval
100
Telaprevir + P/R
Boceprevir + P/R
SVR12 (%)
80
60
53
40
51
41
40
40
32
29
20
n/N =
0
118/
295
79/
190
Overall
61/
116
43/
85
Relapsers
43/
135
32/
80
Partial Response
8/
28
1/9
Null Response
Previous Response to P/R
Fontaine H, et al. EASL 2013. Abstract 60.
11
與蛋白酶抑制劑交互反應的藥物
 HCV PIs are CYP3A4 inhibitors
– Approximately one half of drugs are metabolized by
CYP3A4
 List of drugs affected by CYP3A4 inhibitors is long
– Consult package insert and review med lists frequently
 Until the drug is specifically studied, magnitude of the
impact of PI on its level is not known
 Exercise caution with ALL coadministered medications
Telaprevir: Take Home
 Administered with full-fat foods
 For treatment-naïve and relapser patients
– 12 wks of TVR + pegIFN/RBV followed by RGT with pegIFN/RBV
– Additional 12 wks if HCV RNA undetectable at Wks 4 and 12; otherwise,
additional 36 wks
– Recommended that all cirrhotics receive T12PR48
 For partial and null responders
– T12PR48
 Futility rules for all patients: stop all therapy if HCV RNA > 1000
IU/mL at wk 4 or 12 or detectable at wk 24
 TVR-associated adverse events: rash, anemia, anorectal
symptoms
Boceprevir: Take Home

Administer with meal or light snack

PegIFN/RBV x 4 wks, then add BOC for up to 44 wks of triple therapy

Key HCV RNA assessments at wks 4, 8, 12, 24

RGT based on wk 8 HCV RNA
–
Treatment-naïve patients may be eligible for 24 wks of triple therapy following lead-in
–
Treatment-experienced patients may be eligible for 32 wks of triple therapy following
lead-in
–
Late or slow responders (ie, detectable at wk 8 but undetectable by wk 24) should receive
32 wks of triple therapy then 12 wks of pegIFN/RBV alone

Stop all therapy if HCV RNA ≥ 100 IU/mL at wk 12 or detectable at wk 24

All compensated cirrhotic patients should receive lead-in then BOC + PR for 44 wks
–

Same regimen should be used for null responders, if considered for treatment
BOC-associated adverse events: anemia, dysgeusia
即將上市DAAs
US FDA Advisory Committee, Oct 24-25, 2013
Unanimous recommendations to approve
Simeprevir (SMV)
Sofosbuvir (SOF)
DAAs Currently in Development (not all-inclusive)
NS3/4A
Inhibitors
First generation:
Telaprevir
Boceprevir
First generation, second wave:
Simeprevir
Faldaprevir (BI 201335)
Asunaprevir
ABT-450/r
Sovaprevir (ACH-1625)
Second generation:
MK-5172
ACH-2684
NS5AA
Inhibitors
Daclatasvir (BMS 790052)
Ledipasvir (GS-5885)
GS-5816
ABT-267
ACH-3102
MK-8742
PPI-668
Samatasvir (IDX719)
NS5B Polymerase
Inhibitors
NI:
Sofosbuvir (GS-7977)
VX-135
NNI:
Deleobuvir (BI
207127)
BMS 791325
GS-9669
TMC 647055
ABT-333
QUEST-1: Simeprevir + P/R RGT in TreatmentNaïve GT 1 HCV
 Randomized, double-blind, placebo-controlled phase III trial
– 12% to 13% had cirrhosis, 56% to 57% had GT 1a HCV
Stratified by
GT 1 subtype,
IL28B genotype
Treatment-naive
pts with
GT 1 HCV
(N = 394)
Wk 12
Simeprevir 150 mg QD
+ P/R*
(n = 264)
Placebo + P/R
(n = 130)
Wk 24
Wk 48
P/R
P/R
P/R
*Response-guided therapy: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable
at Wk 12 received a total of 24 wks of therapy. Those not achieving this on-treatment response
received 48 wks of therapy.
P/R, peginterferon alfa-2a 180 µg/wk + ribavirin 1000-1200 mg/day.
Jacobson IM, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.
QUEST-1: Virologic Response to Simeprevir +
P/R Treatment
Virologic Outcomes
SMV + P/R
P/R
SVR12 by RGT Group
85% of pts in SMV arm met RGT criteria
80
100
80
60
50
40
20
0
91
80
80
n/ 202/
N = 254
Wk 4
12
SVR12 (%)
HCV RNA Undetectable (%)
100
60
40
21
20
210/ 65/
264 130
SVR12
0
n/
N=
203/224
6/28
24 Wks
48 Wks
SMV Arm: Total Duration of RGT
Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.
QUEST-1: SVR12 by Fibrosis Level, Subtype,
and Baseline Resistance
100
100
SMV + P/R
P/R
82
80
SVR12 (%)
SVR12 (%)
80
60
90
58
53
40
29
71
60
52
49
40
20
20
n/N = 188/229 60/113
18/31
5/17
105/147 36/74
105/117
29/56
0
0
No Cirrhosis
GT 1a
Cirrhosis
Differences in SVR12 by Subgroup (95% CIs)
GT 1a/other HCV
With baseline Q80K vs Pbo
Without baseline Q80K vs Pbo
GT 1b HCV
-100
-50
Favors Placebo
28.2 (13.4-42.9)
4.7 (-14.6 to 24.1)
40.3 (25.8-54.8)
42.1 (26.5-57.6)
0
50
Favors SMV
100
Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.
GT 1b
SMV (n) Pbo (n)
147
60
86
117
74
74
74
56
QUEST-2: Simeprevir + P/R RGT in TreatmentNaïve GT 1 HCV
 Phase III, randomized, double-blind, placebo-controlled trial

7% to 11% had cirrhosis, 58% had GT 1b HCV
Randomized 2:1*;
stratified by GT 1 subtype,
IL28B genotype
Treatment-naive
pts with GT 1 HCV
(N = 391)
Wk 12
Simeprevir 150 mg QD +
P/R†
(n = 257)
Placebo + P/R
(n = 134)
Wk 24
Wk 48
P/R
P/R
P/R
*63% of patients in each arm were randomly assigned to receive pegIFN alfa-2a or pegIFN alfa-2b;
the remainder were assigned pegIFN alfa-2a.
†RGT: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable at Wk 12 received a
total of 24 wks of therapy. Those not achieving this on-treatment response received 48 wks of
therapy.
Manns M, et al. EASL 2013 Abstract 1413.
QUEST-2: Virologic Response to Simeprevir +
P/R Treatment
SMV + P/R
P/R
100
81
86
SVR12 (%)
80
60
91% of pts in SMV
arm met RGT
criteria
50
40
32
20
n/N =
209/257
67/134
202/235
7/22
0
Overall
24 wks
48 wks
SMV Arm: Total
Duration of RGT
Manns M, et al. EASL 2013. Abstract 1413.
QUEST-2: SVR12 by Subtype and Fibrosis Level

Higher rates of SVR12 with SMV, irrespective of HCV genotype or
cirrhosis

Baseline Q80K mutation not a predictor of response (unlike in QUEST-1)
SMV + P/R
P/R
100
SVR12 (%)
80
82
82
80
65
60
53
46
51
40
40
20
0
86/
n/N = 107
26/
57
GT 1a
123/ 41/
150 77
GT 1b
Manns M, et al. EASL 2013. Abstract 1413.
189/ 61/
231 119
No Cirrhosis
11/
17
6/
15
Cirrhosis
Summary of Simeprevir

RGT met in 85-91% of patients; 86-91% had SVR

Q80K polymorphism in G1a affected SVR in QUEST-1 and in pooled analysis

Safety profiles similar between groups through first 12 wks of treatment
–
No increase in anemia with SMV; slightly higher rash or photosensitivity
–
Mild, transient bilirubin increases with SMV; other liver parameters did not change
QUEST-1[1]
AEs During First 12 Wks, %
QUEST-2[2]
SMV + PR
(n = 264)
PR
(n = 130)
SMV + PR
(n = 257)
PR
(n = 134)
Grade 1/2 AEs
72
65
70
73
Grade 3/4 AEs
23
29
26
24
Serious AEs
3
4
2
2
AEs leading to SMV/placebo discontinuation
3
3
2
1
AEs of interest

Pruritus
21
11
19
15

Rash (any type)
27
25
24
11

Anemia
16
11
14
16

Bilirubin increase
9
4
NR
NR

Photosensitivity conditions
3
1
4
1
Jacobson I, et al. EASL 2013. Abstract 1425; Manns M, et al. EASL 2013. Abstract 1413.
NEUTRINO: Sofosbuvir + P/R for 12 Wks in
Treatment-Naïve GT 1/4/5/6 HCV Patients
 Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for
12 wks in treatment-naive patients with GT 1/4/5/6 HCV
HCV RNA < LLOQ (%)
– 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2%
had GT 6 HCV
100
99
99
90
80
60
40
20
n/N = 321/325
326/327
295/327
EOT
SVR12
0
Wk 4
P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day
Lawitz E, et al. NEJM 2013;368:1878-87.
NEUTRINO: SVR12 With Sofosbuvir + P/R
According to Genotype and Fibrosis Level
SVR12 According to
Fibrosis Level
SVR12 According to
Genotype
100
89
96
100
100
SVR12 (%)
SVR12 (%)
80
80
80
60
40
20
n/N
0 =
92
60
40
20
261/292
27/28
252/273
7/7
43/54
0
GT 1
GT 4
Lawitz E, et al. NEJM 2013;368:1878-87.
GT 5,6
No
Cirrhosis
Cirrhosis
FISSION: Sofosbuvir/RBV vs PegIFN/RBV in
Treatment-Naïve GT 2/3 HCV Patients
 Randomized, controlled, open-label phase III noninferiority trial
– 20% to 21% had cirrhosis; 72% had GT 3 HCV
Stratified by HCV GT (2 vs 3),
HCV RNA (< vs ≥ 106 IU/mL),
cirrhosis (yes vs no)
Treatment-naive
patients with
GT 2/3 HCV
(N = 499)
Wk 12
Sofosbuvir 400 mg QD
+ RBV 1000-1200 mg/day
(n = 256)
PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day
(n = 243)
Gane E, et al. EASL 2013. Abstract 5.
Wk 24
FISSION: Sofosbuvir/RBV Noninferior to P/R in
Tx-Naïve GT 2/3 HCV Patients
Sofosbuvir + RBV
99
99
100
HCV RNA < LLOQ (%)
PegIFN + RBV
99
92
80
P < .001
67
67
67
60
40
20
n/N = 249/250 158/236
242/244 207/224
NA
188/190
170/253 162/243
0
Wk 4
Wk 12
On Treatment
Gane E, et al. EASL 2013. Abstract 5.
Wk 24
SVR12
FISSION: SVR12 According to Genotype and
Fibrosis Level
Sofosbuvir + RBV
100
PegIFN + RBV
98
91
82
SVR12 (%)
80
71
62
61
60
40
34
30
20
n/N =
0
58/59
44/54
No Cirrhosis
10/11
Cirrhosis
Genotype 2
Gane E, et al. EASL 2013. Abstract 5.
8/13
89/145
99/139
No Cirrhosis
13/38
11/37
Cirrhosis
Genotype 3
FISSION: Better Tolerability Profile With
Sofosbuvir/RBV vs PegIFN/RBV

Grade ≥ 3 AEs: 7% with SOF/RBV vs 19% for pegIFN/RBV

Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegIFN/RBV
AEs Occurring in ≥ 15% in
Either Arm, %
Fatigue
Headache
Nausea
Insomnia
Rash
Diarrhea
Irritability
Decreased appetite
Myalgia
Pruritus
Influenzalike symptoms
Chills
Gane E, et al. EASL 2013. Abstract 5.
SOF/RBV
(n = 256)
36
25
18
12
9
9
10
7
8
7
3
3
PegIFN/RBV
(n = 243)
55
44
29
29
17
17
17
18
17
17
18
18
P Value
< .0001
< .0001
.0057
< .0001
.0052
.0075
.0328
.0001
.0060
.0009
< .0001
< .0001
FUSION: Sofosbuvir + RBV for 12 or 16 Wks in
Tx-Experienced GT 2/3 HCV Pts
 Randomized, double-blind, placebo-controlled phase III trial
– 62% to 64% had GT 3 HCV, 33% to 35% had cirrhosis, 75% to 76%
were previous relapsers
Stratified by
HCV GT (2 vs 3),
cirrhosis (yes vs no)
Treatmentexperienced pts with
GT 2/3 HCV
(N = 201)
Wk 12
Sofosbuvir 400 mg QD +
RBV 1000-1200 mg/day
(n = 103)
Nelson D, et al. EASL 2013. Abstract 6.
Sofosbuvir 400 mg QD +
RBV 1000-1200 mg/day
(n = 98)
Wk 16
Placebo
FUSION: Overall Efficacy Outcomes of
Sofosbuvir + RBV in GT 2/3
Sofosbuvir + RBV 12 wks
HCV RNA < LLOQ (%)
100
97
98
100
Sofosbuvir + RBV 16 wks
100
80
73
60
50
40
20
0
n/N = 97/100 93/95
Wk 4
Nelson D, et al. EASL 2013. Abstract 6.
100/100 95/95
50/100 69/95
End of Treatment
SVR12
FUSION: SVR12 With Sofosbuvir + RBV
by Genotype and Fibrosis Level
Sofosbuvir + RBV 12 wks
100
96
100
100
78
80
80
63
60
SVR12 (%)
SVR12 (%)
Sofosbuvir + RBV 16 wks
60
40
20
60
40
37
19
20
n/N = 25/26 23/23
6/10
7/9
0
61
14/38 25/40
5/26 14/23
No Cirrhosis
Cirrhosis
0
No Cirrhosis
Cirrhosis
Genotype 2
Nelson D, et al. EASL 2013. Abstract 6.
Genotype 3
POSITRON: Sofosbuvir + RBV for 12 Wks in GT
2/3 IFN-Unwilling/Intolerant/Ineligible
 Randomized, double-blind, placebo-controlled phase III trial
Stratified by
cirrhosis (yes vs no)
IFN unwilling,
intolerant, or
ineligible pts with GT
2/3 HCV
(N = 278)
Jacobson I, et al. EASL 2013. Abstract 61.
Wk 12
Sofosbuvir 400 mg QD +
RBV 1000-1200 mg/day
(n = 207)
Placebo
(n = 71)
POSITRON: Virologic Response in GT 2/3 IFNUnwilling/Intolerant/Ineligible
Overall Outcomes
100
100
78
80
60
40
20
0
202/
n/N =
204
Wk 4
202/
202
161/
207
EOT
SVR12
 SVR12 0% for placebo
Jacobson I, et al. EASL 2013. Abstract 61.
92
Cirrhosis
94
80
SVR12 (%)
HCV RNA < LLOQ (%)
100
99
No
cirrhosis
68
60
40
21
20
0
85/92 16/17
57/84 3/14
GT 2
GT 3
Topline Summary of Sofosbuvir Trials
Trial
n
Regimen
Duration, Wks
SVR12, %
Tx-naive GT 1
292
SOF + P/R
12
89
NEUTRINO[1] Tx-naive GT 4
28
SOF + P/R
12
96
Tx-naive GT 5/6
7
SOF + P/R
12
100
Tx-naive GT 2
70
SOF + RBV
12
97
Tx-naive GT 3
183
SOF + RBV
12
56
Tx-experienced GT
2
36
SOF + RBV
12
86
Tx-experienced GT
3
64
SOF + RBV
12
30
Tx-experienced GT
2
32
SOF + RBV
16
94
Tx-experienced GT
3
63
SOF + RBV
16
62
IFN-UII GT 2
109
SOF + RBV
12
93
IFN-UII GT 3
98
SOF + RBV
12
61
FISSION[2]
FUSION[3]
POSITRON[4]
Patient Population
1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Gane E, et al. EASL 2013. Abstract 5.
3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61.
STARTVerso1: Faldaprevir + P/R RGT in
Treatment-Naïve in GT 1 HCV
 Final results of phase III STARTVerso1 trial
– 78% were white, 81% Europe, 19% Japan; 66% had GT 1b HCV;
39% had IL28B CC; 6% were cirrhotic
Wk 12
Faldaprevir 120 mg QD
+ P/R* (n = 261)
Treatment-naive
patients with
GT 1 HCV
(N = 656)
Faldaprevir 240 mg QD
+ P/R (n = 262)
Wk 24
Wk 48
Placebo + P/R
Faldaprevir + P/R
Placebo + P/R†
Placebo + P/R
(n = 133)
P/R
P/R
P/R
*RGT: At Wk 12, patients with ETS continued P/R to Wk 24; patients without ETS continued triple therapy
to Wk 24 followed by P/R to Wk 48.
†RGT: At Wk 24, patients with ETS stopped treatment; patients without ETS continued P/R to Wk 48.
ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8.
Ferenci P, et al. EASL 2013. Abstract 1416.
STARTVerso1: SVR12 According to ETS,
Genotype, and Fibrosis Level
100
87 89
SVR12 (%)
Patients (%)
80
FDV 120 mg
FDV 240 mg
Placebo
100
89
86
84
81
80
69
60
40
56
36
20
20
0
60
60
40
67
n/ 226/ 233/
N = 259 261
194/ 208/
226 233
Achieved
ETS
SVR12 in
ETS Pts
0
60/ 16/
87 45
143/ 52/
171 86
172/
212
30/
45
9/
16
GT 1a
GT 1b
< F3
≥ F3
F4
ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8.

23% of pts with GT 1a HCV had Q80K at baseline; not predictive of
SVR12
Ferenci P, et al. EASL 2013. Abstract 1416.
Summary of Safety Data with Faldaprevir

FDV + PR relatively safe and well tolerated
–

Most frequent AEs: gastrointestinal events, rash, and jaundice
Transient, dose-dependent bilirubin increases, primarily in FDV 240-mg arm
–
Not associated with concomitant increases in other liver parameters
Safety Outcome, %
FDV 120 mg + PR
(n = 259)
FDV 240 mg + PR
(n = 261)
PR
(n = 132)
Serious AE
7
7
6
AEs leading to discontinuation of all drugs
4
5
4
AEs leading to discontinuation of FDV or placebo
1
3
0
Grade 2-4 AEs*
52
55
48

Anemia
13
12
11

Gastrointestinal events
7
12
3

Rash
8
9
6

Jaundice
2
3
0

Photosensitivity
0
1
0
12
53
1
32
33
22
8
9
6
Grade 3/4 laboratory abnormalities*

Total bilirubin
Rash

Grade 2-4 rash*
Ferenci P, et al. EASL 2013. Abstract 1416.
*AEs graded according to Division of AIDS grading system.
Summary of Safety Findings From
Phase III Trials
 Sofosbuvir[1-4]
– Generally well tolerated; low rates of grade 3/4 AEs, serious AEs, and
treatment discontinuation due to AEs; improved profile with
SOF/RBV vs pegIFN/RBV
 Greatly improved Hb profile with simeprevir and faldaprevir vs
boceprevir/telaprevir with no significant increase over
pegIFN/RBV[5-7]
 Simeprevir[5,6]
– Generally well tolerated; no added safety signals with triple therapy
 Faldaprevir[7]
– Generally well tolerated (clinically benign and transient bilirubin
increases with 240 mg dose; higher incidence of gastrointestinal
events and rash)
1. Lawitz E, et al. NEJM 2013;368:1878-87. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al.
EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013.
Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract
1416.
Summary of Resistance Findings From Phase III
Trials
 Sofosbuvir[1-4]
– No S282T mutations identified; other NS5B genetic variants not
associated with change in phenotypic susceptibility
 Simeprevir[5,6]
– Baseline Q80K polymorphism present in 41% of patients with GT 1a
HCV and associated with lower SVR12 rate in QUEST-1[5]
– Emergent NS3 protease mutations in > 90% of patients without SVR
(GT 1a: R155K alone, with mutations at positions 80 and/or 168;
GT 1b: most common mutation D168V, Q80R + D168E)[5,6]
 Faldaprevir[7]
– Baseline Q80K present in 23% of patients with GT 1a HCV but not
associated with SVR12 rate
1. Lawitz E, et al. NEJM 2013;368:1878-87. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al.
EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013.
Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract
1416.
Summary of DAAs Clinical TrialsUp to 2013-10
Triple DAA with Peg-IFN + RBV Therapy for Untreated
and Treated HCV Patients
Study
Patients
Treatment
Drug class
SVR (%)
PILLAR
G1, naïve
SMV vs. Placebo
PI
86 vs. 65
SILEN-C1
G1, naïve
FDV vs. Placebo
PI
83 vs. 56
ATLAS
G1, naïve
DNVr vs. Placebo
PI
83 vs. 43
MATTERHORN
G1, partial
DNVr
PI
56
NEXT-1
G1, naïve
Narlaprevir vs. placebo
PI
85 vs. 28
MK-7009
G1, naive
VNR vs. placebo
PI
61-84 vs. 63
ABT-450
G1, naive
ABT450r vs. placebo
PI
88 vs. 9
AI447016
G1, naive
ASV vs. placebo
PI
92 vs. 46
COMMAND-1
G1, naive
DCV vs. placebo
NS5A
83 vs. 25
D-LITE
G1, naive
DCV
NS5A
76
PROTON
G1, naive
SOF vs. placebo
NI
91 vs. 58
ATOMIC
G1, naive
SOF
NI
97
NEUTRINO
G1, naïve
SOF
NI
90
ELECTRON
G2/3, naïve
SOF
NI
100
JUMP-C
G1, naïve
MCB vs. placebo
NI
58 vs. 36
ESSENTIAL
G1. naïve
ALV
CI
76 vs. 55
Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76
Quadruple DAA with Peg-IFN + RBV Therapy for
Untreated and Treated HCV Patients
Study
Patients
Treatment
Drug class
SVR (%)
ZENITH
G1, naïve
TVR, VX-22
PI, NNPI
83-90
AI447017
G1, null
ASV, DCV
PI, NS5A
95
GILEAD
G1, naïve
GS-9256, tegobuvir
PI, NNPI
98
MATTERHORN
G1 partial
DNVr, MCB
PI, NI
86
G1, null
DNVr, MCB
PI, NI
84
Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76
IFN Free Therapy for Untreated and Treated HCV
Patients
Study
Patients
Treatment
Drug class
SVR (%)
Triple DAA
G1, naïve
ASV, DCV, BMS-791325
PI, NS5A, NNPI
94
Lok
G1, null
ASV, DCV
PI, NS5A
36
Co-Pilot
G1, naïve
ABT450r, ABT333, RBV
PI, NNPI, RBV
95
G1, NR
ABT450r, ABT333, RBV
PI, NNPI, RBV
47
Pilot
G1, naïve
ABT-450r, ABT072, RBV
PI, NNPI, RBV
91
AVIIATOR
G1, naïve
ABT450r, ABT267, ABT333, RBV
PI, NS5A, NNPI, RBV
97
G1, null
ABT450t, ABT267, ABT333, RBV
PI, NS5A, NNPI, RBV
36
G1, naïve
DNVr, MCB
PI, NI
G1, naïve
DNVr, MCB, RBV
PI, NI, RBV
41
G1b, partial
DNVr, MCB, RBV
PI, NS5A, RBV
39
G1b, null
DNVr, MCB, RBV
PI, NI, RBV
55
G1a, naïve
Faldaprevir, BI207127, RBV
PI, NNPI, RBV
43
G1b, naïve
Faldaprevir, BI207127, RBV
PI, NNPI, RBV
83
G1, cirrhosis
Faldaprevir, BI207127, RBV
PI, NNPI, RBV
54-57
G2/3, naïve
ALV, RBV
CI, RBV
INFORM
MATTERHORN
SOUND-C2
VITAL-1
Discontinued
88
Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76
IFN Free Therapy for Untreated and Treated HCV
Patients
Study
AI444-04
Patients
Treatment
Drug class
SVR (%)
G1, naïve
DCV, SOF
NS5A, NI
100
G1, naïve
DCV, SOF, RBV
NS5A, NI, RBV
100
G2/3, naïve
DCV, SOF
NS5A, NI
G2/3, naïve
DCV, SOF, RBV
NA5A, NI, RBV
G1, naïve
SOF, RBV
NI, RBV
G1, naïve
GS5885, RBV
NS5A, RBV
100
G2/3, naïve
SOF, RBV
NI, RBV
100
G1, null
SOF, RBV
NI, RBV
10, 10
G1, null
GS5885, SOF, RBV
NS5A, NI, RBV
G2/3, experienced
SOF, RBV
NI, RBV
80, 68
FISSION
G2/3, naïve
SOF, RBV
NI, RBV
67
FUSION
G2/3, experienced
SOF, RBV
NI, RBV
50, 73
POSITRON
G2/3, ineligible,
intolerant, unwilling
SOF, RBV
NI, RBV
78
Gilead-QUAD
G1, naïve
GS9451, GS5885, GS9190, RBV
PI, NS5A, NNPI, RBV
100
ELECTRON
88-100
86
88, 84
100
Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76

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