1 sheng-shun yang, m.d., ph.d. division of gastroenterology & hepatology, department of internal...
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1
Sheng-Shun Yang, M.D., Ph.D.
Division of Gastroenterology & Hepatology,
Department of Internal Medicine,
Taichung Veterans General Hospital, Taichung, Taiwan
2013-11-28
Direct Acting Antivirals for Chronic Hepatitis C
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.
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
治療 C 型肝炎的目標
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
0
20
40
60
80
100
IFN 6m IFN 12m IFN / RBV 6 m IFN / RBV 12m PEG-IFN 12m PEG-IFN / RBV 12m
PEG-IFN / RBV /DAA 12m
Su
stai
ne
d V
iro
log
ic R
esp
on
se (
%)
6%
13-19%
31-35%38-43%
45-47%
54-63%
68-75%
1992 2001-2010 2011
SVR rates remain suboptimal in HCV genotype 1
Response-guided therapy (RGT): ~2004
IL28B genotypes: ~2009
Direct acting antivirals (DAAs):
~2011
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;56:532-43Kraus MR, et al. Hepatology 2013;58:497-504; Brandman et al. Diabetes Care 2012;35(5):1090-4Van der Maar, et al. JAMA 2012;308:2584-93.
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.
Modified from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
SVR, %
IFN Monotherapy
PegIFNPegIFN+ 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
當前 C 型肝炎標準療法及療效
目前治療成效不錯我們還需要 DAAs 嗎 ?
Multiple AEs from SOCNull/partial responders, relapsers
Unwilling, intolerant, ineligible‘Difficulty-to-treat’ (cirrhotics, HIV coinfected, post LT
recurrent, renal transplant candidates & HCV infected post kidney transplantation)
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
Response-Guided Therapy
Treatment-naïve patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to wk 48)
No eRVR; PegIFN + RBV
Telaprevir + pegIFN/RBV 用於基因第一型未曾治療過的病患
TVR + PegIFN + RBV
Wks 480 24124
eRVR; stop at Wk 24, f/u 24 wksPegIFN + RBV
*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
Telaprevir [package insert]. May 2011. Vertex/Johnson & Johnson's Incivo.
HCV RNA TVR + PegIFN/RBV PegIFN/RBV TotalDuration
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
F/u 24 wks
Telaprevir + PR: 基因第一型未曾治療過的病患之持續病毒反應率
SVR
75
44
P < .001
SV
R (
%)
0
20
40
60
80
100T12PRPR
ADVANCE: TVR + PegIFN/RBV in Treatment-Naïve Genotype 1
271/363 158/361n/N =
Jacobson IM, et al. NEJM 2011;364:2405-2416.
Telaprevir + PR: 副作用 Higher rates of rash, anemia, and anorectal signs/symptoms in TVR
arms vs control
Anorectal symptom management
– Fiber, loperamide, hydrocortisone, and pramoxine topical cream
Adverse Event, % TVR + PR RGT/48*(n = 1797)
PR48 (n = 493)
Rash 56 34
Anemia† 36 17
Anorectal events 29 7
Telaprevir package insert. May 2011.
*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.
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
Response-Guided Therapy* 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
F/u 24 wks
Boceprevir + PegIFN + RBV
Wks480 28124
PegIFN + RBV
*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
PegIFN + RBV
8 36
Boceprevir + PegIFN + RBV
Boceprevir [package insert]. May 2011. Merck & Co’s Victrelis.
24
F/u 24 wks
Boceprevir + PR: 持續病毒反應率
P < .001
P < .001
Nonblack Patients
P = .04
P = .004
Black Patients
125/311
211/316
213/311
12/52
22/52
29/55
Poordad F, et al. NEJM 2011;364:1195-1206.
SPRINT-2: BOC + PegIFN/RBV in Genotype 1 Treatment-Naïve Patients
SV
R (
%)
PR48 BOC RGT
100
80
60
40
20
0BOC/PR48
40
67 68
SV
R (
%)
PR48 BOC RGT
100
80
60
40
20
0BOC/PR48
23
4253
n/N = n/N =
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.
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
Treatment duration 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
F/u 24 wks
TVR + PegIFN + RBV
Wks480 24124
PegIFN + RBV
Telaprevir [package insert]. May 2011.
100
0
60
SV
R (
%)
80
40
Telaprevir 使用於過去治療失敗者的療效
Lead-in examined, but found to have no impact on response and not used in TVR label
Previous Relapsers Previous Partial Responders
n/N =
Previous Null Responders
*P < .001 vs placebo/PR48.
REALIZE: TVR + PegIFN/RBV in Genotype 1 Previous Relapsers and Nonresponders
4/2729/49 26/48 2/3721/72 25/7516/68121/145 124/141
Zeuzem S, et al. NEJM 2011;364:2417-2428.
20
83*88*
24
59*54*
15
29*33*
5
T12/PR48 Pbo/PR48LI T12/PR48
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
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
F/u 24 wks
Boceprevir + PegIFN + RBV
Wks480 28124
PegIFN + RBV
*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
PegIFN + RBV
8 36
Boceprevir + PegIFN + RBV
Boceprevir [package insert]. May 2011.
24
BOC + PR: SVR by Historical Response (Partial Responders and Relapsers*)
*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.
RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients
2/29 23/57 30/58 2/29 23/57 30/58
SV
R (
%)
Partial Responder
100
80
60
40
20
0
7
Relapser
40
52
29
6975
PR48 (n = 80)
BOC RGT (n = 162)
BOC/PR48 (n = 161)
n/N =
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
Fontaine H, et al. EASL 2013. Abstract 60.
n/N =118/295
79/190
61/116
43/85
43/135
32/80
8/28 1/9
100
80
60
40
20
0
SV
R12
(%
)
Overall Relapsers Partial Response Null Response
40 41
53 51
3240
29
11
Telaprevir + P/RBoceprevir + P/R
Previous Response to P/R
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)
NS3/4AInhibitors
NS5AAInhibitors
NS5B Polymerase Inhibitors
First generation:TelaprevirBoceprevirFirst generation, second wave:SimeprevirFaldaprevir (BI 201335)AsunaprevirABT-450/rSovaprevir (ACH-1625)Second generation:MK-5172ACH-2684
Daclatasvir (BMS 790052)Ledipasvir (GS-5885)GS-5816ABT-267ACH-3102MK-8742PPI-668Samatasvir (IDX719)
NI:Sofosbuvir (GS-7977)VX-135NNI:Deleobuvir (BI 207127)BMS 791325GS-9669TMC 647055ABT-333
QUEST-1: Simeprevir + P/R RGT in Treatment-Naïve GT 1 HCV
Randomized, double-blind, placebo-controlled phase III trial
– 12% to 13% had cirrhosis, 56% to 57% had GT 1a HCV
Jacobson IM, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.
Simeprevir 150 mg QD + P/R*
(n = 264)Treatment-naive pts with
GT 1 HCV(N = 394)
Stratified by GT 1 subtype, IL28B genotype
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.
P/R Placebo + P/R
(n = 130)
Wk 24 Wk 48Wk 12
QUEST-1: Virologic Response to Simeprevir + P/R Treatment
85% of pts in SMV arm met RGT criteria
Virologic Outcomes
24 Wks 48 Wks
Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.
210/264
n/N =
65/130 203/224 6/28
202/254
80
60
40
20
0
100
HC
V R
NA
Und
etec
tabl
e (%
)
Wk 4 SVR12
80
12
80
50
SMV + P/R P/R
80
60
40
20
0
SV
R12
(%
)
100 91
21
SVR12 by RGT Group
SMV Arm: Total Duration of RGT
n/N =
QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance
Jacobson I, et al. EASL 2013 Abstract 1425; AASLD 2013 Abstract 1122.
Differences in SVR12 by Subgroup (95% CIs)
GT 1a/other HCV With baseline Q80K vs Pbo Without baseline Q80K vs PboGT 1b HCV
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)
1476086117
74747456
SMV (n) Pbo (n)
Favors Placebo Favors SMV-100 -50 0 50 100
18/31n/N = 5/17188/229
60/113
82
5358
29
SMV + P/RP/R
100
80
60
40
20
0
SV
R1
2 (
%)
No Cirrhosis Cirrhosis
105/117 29/56105/147
36/74
71
49
90
52
100
60
20
0
SV
R1
2 (
%)
GT 1a GT 1b
80
40
Treatment-naive pts with GT 1 HCV
(N = 391)
Simeprevir 150 mg QD +P/R†
(n = 257)
Randomized 2:1*; stratified by GT 1 subtype,
IL28B genotype
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.
Placebo + P/R(n = 134)
P/R
P/R
QUEST-2: Simeprevir + P/R RGT in Treatment-Naïve GT 1 HCV
Phase III, randomized, double-blind, placebo-controlled trial
7% to 11% had cirrhosis, 58% had GT 1b HCV
Wk 24 Wk 48Wk 12
Manns M, et al. EASL 2013 Abstract 1413.
QUEST-2: Virologic Response to Simeprevir + P/R Treatment
Manns M, et al. EASL 2013. Abstract 1413.
SMV Arm: Total Duration of RGT
91% of pts in SMV arm met RGT
criteria
n/N =
SMV + P/RP/R
Overall 24 wks 48 wks
100
80
60
40
20
0
SV
R12
(%
)
81
50
86
32
209/257 67/134 202/235 7/22
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)
Manns M, et al. EASL 2013. Abstract 1413.
86/107
26/57
123/150
41/77
189/231
61/119
11/17
6/15n/N =
GT 1a No Cirrhosis Cirrhosis
100
80
60
40
20
0
SV
R12
(%
)
80
46
82
65
SMV + P/RP/R
GT 1b
82
53 5140
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
AEs During First 12 Wks, % QUEST-1[1] 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
– 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV
Lawitz E, et al. NEJM 2013;368:1878-87.
P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day
HC
V R
NA
< L
LOQ
(%
) 99 9990100
80
60
40
20
0Wk 4 EOT SVR12
321/325 326/327 295/327n/N =
NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level
Lawitz E, et al. NEJM 2013;368:1878-87.
SV
R12
(%
)
92
80
100
80
60
40
20
0No
CirrhosisCirrhosis
252/273 43/54
SVR12 According to Fibrosis Level
SV
R12
(%
)
8996
100100
80
60
40
20
0GT 1 GT 4 GT 5,6
261/292 27/28 7/7
SVR12 According to Genotype
n/N =
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
Gane E, et al. EASL 2013. Abstract 5.
Treatment-naive patients with GT 2/3 HCV
(N = 499)
Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day
(n = 256)
PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day(n = 243)
Wk 24Wk 12
Stratified by HCV GT (2 vs 3), HCV RNA (< vs ≥ 106 IU/mL),
cirrhosis (yes vs no)
FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naïve GT 2/3 HCV Patients
Gane E, et al. EASL 2013. Abstract 5.
P < .001
SVR12
On Treatment
249/250 158/236 242/244 207/224
Wk 4 Wk 24
HC
V R
NA
< L
LOQ
(%
)
188/190NA
Wk 12
170/253 162/243n/N =
Sofosbuvir + RBV PegIFN + RBV
100
80
60
40
20
0
99
67
99 9992
67 67
FISSION: SVR12 According to Genotype and Fibrosis Level
Gane E, et al. EASL 2013. Abstract 5.
Genotype 2 Genotype 3
SV
R12
(%
)
No Cirrhosis No CirrhosisCirrhosis Cirrhosis
58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37n/N =
100
80
60
40
20
0
98
8291
62 6171
34 30
Sofosbuvir + RBV PegIFN + RBV
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
Gane E, et al. EASL 2013. Abstract 5.
AEs Occurring in ≥ 15% in Either Arm, %
SOF/RBV(n = 256)
PegIFN/RBV(n = 243)
P Value
Fatigue 36 55 < .0001
Headache 25 44 < .0001
Nausea 18 29 .0057
Insomnia 12 29 < .0001
Rash 9 17 .0052
Diarrhea 9 17 .0075
Irritability 10 17 .0328
Decreased appetite 7 18 .0001
Myalgia 8 17 .0060
Pruritus 7 17 .0009
Influenzalike symptoms 3 18 < .0001
Chills 3 18 < .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
Nelson D, et al. EASL 2013. Abstract 6.
Treatment-experienced pts with
GT 2/3 HCV(N = 201)
Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day
(n = 103)
Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day
(n = 98)
Wk 16Wk 12
Placebo
Stratified by HCV GT (2 vs 3),
cirrhosis (yes vs no)
FUSION: Overall Efficacy Outcomes of Sofosbuvir + RBV in GT 2/3
Nelson D, et al. EASL 2013. Abstract 6.
97/100 93/95 100/100 95/95
Wk 4 End of Treatment
HC
V R
NA
< L
LOQ
(%
)
SVR12
50/100 69/95n/N =
Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks
100
80
60
40
20
0
97 98 100 100
50
73
FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level
Nelson D, et al. EASL 2013. Abstract 6.
6/10 5/26
SV
R12
(%
)
25/26 7/923/23 14/38 14/2325/40
No Cirrhosis
Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks
No CirrhosisCirrhosis Cirrhosis
Genotype 2 Genotype 3
19
6163
37
n/N =
100
80
60
40
20
0
96 100
60
78
100
80
60
40
20
0
SV
R12
(%
)
POSITRON: Sofosbuvir + RBV for 12 Wks in GT 2/3 IFN-Unwilling/Intolerant/Ineligible
Randomized, double-blind, placebo-controlled phase III trial
Jacobson I, et al. EASL 2013. Abstract 61.
IFN unwilling, intolerant, or
ineligible pts with GT 2/3 HCV (N = 278)
Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day
(n = 207)
Placebo(n = 71)
Wk 12Stratified by cirrhosis (yes vs no)
POSITRON: Virologic Response in GT 2/3 IFN-Unwilling/Intolerant/Ineligible
SVR12 0% for placebo
Jacobson I, et al. EASL 2013. Abstract 61.
202/204
202/202
Wk 4 EOT
HC
V R
NA
< L
LOQ
(%
)
SVR12
161/207n/N =
Overall Outcomes
GT 2 GT 3
SV
R12
(%
)85/92 16/17 57/84 3/14
No cirrhosis
Cirrhosis
100
80
60
40
20
0
99 100
78
100
80
60
40
20
0
92 94
68
21
Topline Summary of Sofosbuvir Trials
Trial Patient Population n Regimen Duration, Wks SVR12, %
NEUTRINO[1]
Tx-naive GT 1 292 SOF + P/R 12 89
Tx-naive GT 4 28 SOF + P/R 12 96
Tx-naive GT 5/6 7 SOF + P/R 12 100
FISSION[2]Tx-naive GT 2 70 SOF + RBV 12 97
Tx-naive GT 3 183 SOF + RBV 12 56
FUSION[3]
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
POSITRON[4]IFN-UII GT 2 109 SOF + RBV 12 93
IFN-UII GT 3 98 SOF + RBV 12 61
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.
Placebo + P/R(n = 133)
Wk 12
*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.
Wk 24 Wk 48
P/R
Ferenci P, et al. EASL 2013. Abstract 1416.
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
Treatment-naive patients with
GT 1 HCV(N = 656)
Faldaprevir 120 mg QD+ P/R* (n = 261)
Faldaprevir 240 mg QD+ P/R (n = 262)
Placebo + P/R†
Faldaprevir + P/R
P/R
Placebo + P/R
P/R
STARTVerso1: SVR12 According to ETS, Genotype, and Fibrosis Level
23% of pts with GT 1a HCV had Q80K at baseline; not predictive of SVR12
Ferenci P, et al. EASL 2013. Abstract 1416.
60/87
16/45
143/171
52/86
172/212
30/45
9/16
FDV 120 mg
n/N =
226/259
233/261
194/226
208/233
100
80
60
40
20
0
Pat
ient
s (%
)
Achieved ETS
SVR12 in ETS Pts
87 89 86 89 100
80
60
40
20
0
SV
R12
(%
)
GT 1a GT 1b
69
36
84
60
FDV 240 mg Placebo
81
67
56
< 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.
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
Ferenci P, et al. EASL 2013. Abstract 1416.
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
Grade 3/4 laboratory abnormalities*
Total bilirubin 12 53 1
Rash 32 33 22
Grade 2-4 rash* 8 9 6
*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.
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
INFORM G1, naïve DNVr, MCB PI, NI Discontinued
G1, naïve DNVr, MCB, RBV PI, NI, RBV 41
MATTERHORN G1b, partial DNVr, MCB, RBV PI, NS5A, RBV 39
G1b, null DNVr, MCB, RBV PI, NI, RBV 55
SOUND-C2 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
VITAL-1 G2/3, naïve ALV, RBV CI, RBV 88
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 (%)
AI444-04 G1, naïve DCV, SOF NS5A, NI 100
G1, naïve DCV, SOF, RBV NS5A, NI, RBV 100
G2/3, naïve DCV, SOF NS5A, NI 88-100
G2/3, naïve DCV, SOF, RBV NA5A, NI, RBV 86
ELECTRON G1, naïve SOF, RBV NI, RBV 88, 84
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 100
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
Dabbouseh NM, et al. Nat Rev Gastroenterol Hepatol 2013;10:268-76